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Survivin is a Therapeutic Target in Ewing Sarcoma
Author(s) -
Dioufa Nikolina,
Tsokos Maria
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.417.6
Subject(s) - survivin , anoikis , sarcoma , cancer research , ewing's sarcoma , medicine , fli1 , inhibitor of apoptosis , intravasation , cancer , cancer cell , biology , apoptosis , programmed cell death , pathology , transcription factor , biochemistry , gene
Ewing sarcoma, a bone and soft tissue sarcoma of young adults, is genetically defined by the EWS/FLI1 fusion. Current treatment is not effective in patients with macro‐ (25%) and micro‐metastatic (30%) disease, which is fatal in 80% of them. Our goal is to study the metastatic phenotype of Ewing sarcoma in order to identify molecules that can predict and be targeted to treat metastatic disease. In order to survive in the circulation and metastasize tumor cells escape anoikis, a form of cell death that occurs when they detach from the extracellular matrix. Therefore, three dimensional spheroid cultures based on anchorage independent survival of tumor cells have been used to study metastatic tumor phenotypes. We established three dimensional spheroid cultures of four Ewing sarcoma cell lines and showed that when compared to their respective adherent cells they 1) show increased chemoresistance and migration in vitro , 2) grow faster and form larger tumors in mice 3) show increased levels of EWS/FLI1 in the blood of mice consistent with circulating tumor cells and 4) have higher levels of survivin, an inhibitor of apoptosis protein with preferential expression in cancer cells. We also showed that survivin has a role in the formation of the spheres and drug‐resistant phenotype, because its downregulation with siRNA and YM155, a small molecule inhibitor currently tested in clinical trials, reversed the sphere formation and chemoresistance. These data support that survivin is a biologic marker of aggressiveness and can be targeted to treat patients with metastatic Ewing sarcoma.